This grant application focuses on hit-to-lead studies that will evaluate a series of hits arising from a cellular high throughput screen that detected inhibitors of Plasmodium falciparum growth in the intra-erythrocytic stages. For each novel hit series, we will explore structure activity relationships that govern potency, cellular selectivity, and efficacy;structure property relationships that govern adsorption, distribution, metabolism, and excretion;and mechanism of action. In each case, the purpose of the studies is to evaluate the potential for the development of each novel series in the context of the existing portfolio of antimalarial drugs and development candidates. The series will be prioritized based upon these studies with the ideal series having novel mechanism of action, high inherent selectivity for Plasmodium versus the human host, and physiochemical properties that are compatible with development of an orally available drug candidate. As such, the project is a perfect adjunct to ongoing MMV support of lead-candidate development as it will provide a pipeline of new inhibitor types for further development. The specific aims of this program are: 1. To validate by re-synthesis and limited structure activity relationship studies as many hits as possible from the SJCRH screen. 2. To execute hit-to-lead studies on at least 5 validated hits, either progressing them to early lead status or disqualifying them from further work. 3. To assess liabilities for each early lead and develop specific plans for their later development. Public Health Relevance: Malaria is one of the most profound existing human health problems with annual morbidity of several hundred million cases worldwide. Although drugs remain the dominant means for treating malaria infections, both prophylactically and curatively, inexpensive, effective drugs such as chloroquine now suffer from worldwide resistance. The development of multiple novel antimalarial chemotypes is the strategy that offers the most promise for circumventing drug resistant malaria in the campaign for disease eradication.